Surfactant-Protein Innate Immunity in an Asthma Model

哮喘模型中的表面活性剂蛋白先天免疫

• 批准号: 6670310
• 负责人: ANGELA HACZKU
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2004-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6670310
• 关键词: Aspergillus; SDS polyacrylamide gel electrophoresis; allergens; alveolar macrophages; antigen presentation; asthma; biofeedback; cell migration; cellular immunity; dendritic cells; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; gene targeting; genetically modified animals; immunocytochemistry; in situ hybridization; inflammation; laboratory mouse; leukocyte activation /transformation; lymph nodes; mucosa; protein biosynthesis; pulmonary surfactants; recombinant proteins; respiratory airway clearance; respiratory epithelium

DESCRIPTION (provided by applicant): Components of the innate immune system are important in regulation of allergic sensitization. Surfactant protein (SP)-D, a constitutively expressed collagen-like lectin in the lung, plays a prominent role in innate host defense by aiding clearance of inhaled pathogens. Our preliminary studies demonstrated a significantly increased expression of this molecule in allergic airway inflammation. Further, SP-D has shown strong inhibitory effects on Th2-type lymphocyte activation suggesting a specific function in development of allergic airway changes. The hypothesis of this proposal states that SP-D protects lung mucosal surfaces by inhibiting allergen-induced events at three different levels: (I). Constitutively secreted SP-D in the air spaces aids clearance of allergens by alveolar macrophages (MP) to prevent development of a productive T cell response. (II). SP-D enhances dendritic cell (DC) migration to promote compartmentalization of the immune response to the lymph nodes. (III). Th2-type immune response enhances SP-D synthesis, which in turn inhibits further T cell activation, providing a negative feedback regulatory loop. Aspergillus fumigatus (Af) extract will be used to sensitize mice in an established model and the effects of SP-D deficiency and recombinant SP-D treatment will be studied. In Aim #1 the role of SP-D will be defined in clearance of Af particles by MPs in vitro and in Af-induced allergic inflammation of SP-D-/- and normal mice in vivo. Aim #2 will delineate whether SP-D is important in promoting DC migration to the lymph nodes using fluorescently labeled DCs in an allergen exposure model. Aim #3 will assess the direct inhibitory effects of SP-D on allergen-induced T cell activation and the ensuing Th2-type immune response. In Aim #4, the Th2-type cytokine induced feedback regulation of SP-D synthesis will be investigated by delineating the cell types and regulatory pathways involved. Results from these studies will extend our understanding of the implications of this pattern recognition molecule in the pathogenesis of fungal-allergen induced asthma, and define a novel connection between the innate and adaptive immune system. The potential opportunity to interfere with allergic sensitization by SP-D treatment bears high clinical significance.

描述（由申请人提供）：先天免疫系统的组成部分对于调节过敏敏化很重要。 表面活性剂蛋白（SP）-d是一种组成型表达的胶原样凝集素，通过协助清除吸入的病原体在先天宿主防御中起着重要作用。 我们的初步研究表明，该分子在过敏性气道炎症中的表达显着增加。 此外，SP-D对Th2型淋巴细胞的激活显示出强烈的抑制作用，这表明在过敏性气道变化的发展中具有特定功能。 该提案的假设指出，SP-D通过抑制过敏原诱导的三个不同级别的事件来保护肺粘膜表面：（i）。空气空间中的组成型分泌的SP-D有助于通过肺泡巨噬细胞（MP）清除过敏原，以防止生产性T细胞反应的发展。 （ii）。 SP-D增强了树突状细胞（DC）迁移，以促进对淋巴结的免疫反应的分区化。 （iii）。 Th2型免疫反应增强了SP-D合成，从而抑制了T细胞的进一步激活，从而提供了负反馈调节环。 曲霉菌（AF）提取物将用于使小鼠在既定模型中敏感，并且将研究SP-D缺乏症和重组SP-D处理的影响。 在AIM＃1中，SP-D的作用将在MPS在体外和AF诱导的SP-D - / - 和正常小鼠体内的过敏性炎症中清除AF颗粒的作用。 AIM＃2将描绘SP-D在使用过敏原暴露模型中使用荧光标记的DC促进直流迁移到淋巴结的迁移是否重要。 AIM＃3将评估SP-D对过敏原诱导的T细胞激活和随后的Th2型免疫反应的直接抑制作用。 在AIM＃4中，将通过描述所涉及的细胞类型和调节途径来研究Th2型细胞因子诱导的SP-D合成反馈调节。 这些研究的结果将扩展我们对这种模式识别分子在真菌 - 过敏原引起的哮喘发病机理中的含义的理解，并定义了先天性和适应性免疫系统之间的新联系。 通过SP-D治疗干扰过敏敏化的潜在机会具有很高的临床意义。